tbuckley/cabot-search huggingface dataset:
Potential Impact of Revised NCI Eligibility Criteria Guidance: Prior Malignancy Exclusion in Breast Cancer Clinical Trials
Authors: Matthew Perez, Caitlin C. Murphy, Sandi L. Pruitt, Sawsan Rashdan, Asal Rahimi, David E. Gerber
Journal: Journal of the National Comprehensive Cancer Network (2022)

Background: Many individuals with cancer have survived a prior cancer and for this reason may have been excluded from clinical trials. Recent NCI guidance recommends including these individuals, especially when the risk of the prior malignancy interfering with either safety or efficacy endpoints is very low. Using breast cancer as an example, we determined the potential effect this policy change may have on clinical trial accrual. Patients and Methods: We reviewed protocols of NCI-sponsored breast cancer clinical trials activated in 1991 through 2016. We quantified prevalence of prior cancer-related exclusion criteria and assessed the association with trial characteristics using Fisher’s exact tests. Using SEER data, we estimated the prevalence and timing of prior primary (nonbreast) cancer diagnoses among patients with breast cancer. Results: Among 87 clinical trials (total target enrollment, 137,253 patients), 77% excluded individuals with prior cancer, most commonly (79%) within the preceding 5 years. Among trials with radiographic response or toxicity endpoints, 69% excluded prior cancer. In SEER data, the prevalence of a prior (nonbreast) cancer diagnosis ranged from 5.7% to 7.7%, depending on breast cancer stage, of which 39% occurred within 5 years of the incident breast cancer. For trials excluding prior cancer, the estimated proportion of patients excluded for this reason ranged from 1.3% to 5.8%, with the estimated number of excluded patients ranging from 1 to 288. Conclusions: More than three-fourths of NCI-sponsored breast cancer clinical trials exclude patients with prior cancer, including almost 70% of trials with response or toxicity endpoints. Given that &gt;5% of patients with breast cancer have a history of prior cancer, in large phase III trials this practice may exclude hundreds of patients. Following recent NCI eligibility guidance, the inclusion of patients with prior cancer on breast cancer trials may have a meaningful impact on accrual.
The potential role of HIV-1 latency in promoting neuroinflammation and HIV-1-associated neurocognitive disorder
Authors: Sheetal Sreeram, Fengchun Ye, Yoelvis Garcia-Mesa, Kien Nguyen, Ahmed El Sayed, Konstantin Leskov, Jonathan Karn
Journal: Trends in Immunology (2022)

Despite potent suppression of HIV-1 viral replication in the central nervous system (CNS) by antiretroviral therapy (ART), between 15% and 60% of HIV-1-infected patients receiving ART exhibit neuroinflammation and symptoms of HIV-1-associated neurocognitive disorder (HAND) - a significant unmet challenge. We propose that the emergence of HIV-1 from latency in microglia underlies both neuroinflammation in the CNS and the progression of HAND. Recent molecular studies of cellular silencing mechanisms of HIV-1 in microglia show that HIV-1 latency can be reversed both by proinflammatory cytokines and by signals from damaged neurons, potentially creating intermittent cycles of HIV-1 reactivation and silencing in the brain. We posit that anti-inflammatory agents that also block HIV-1 reactivation, such as nuclear receptor agonists, might provide new putative therapeutic avenues for the treatment of HAND.
The Role of Immunotherapy in the Management of Soft Tissue Sarcomas: Current Landscape and Future Outlook
Authors: Lauren B. Banks, Sandra P. D’Angelo
Journal: Journal of the National Comprehensive Cancer Network (2022)

Soft tissue sarcomas (STS) are a subset of sarcoma, a rare group of heterogeneous malignancies of mesenchymal origin. Current standard of care involves surgical resection with systemic chemotherapy used to treat high-risk localized and metastatic disease. Though classically thought to be immunologically quiet tumors, STS interact with the immune system, undergoing immunoediting that alters tumor immunogenicity and the tumor microenvironment. Recent advances with immune checkpoint inhibition have led to clinical trials exploring the efficacy of immunotherapy in treating STS. Results from these trials point to histologic subtype–specific clinical activity of immune checkpoint blockade. In addition, combinatorial strategies adding immune checkpoint inhibition to local or systemic therapies for STS have further increased their efficacy. Targeted immunotherapies using engineered T-cell receptor–based approaches also show increasing promise as treatment options for some patients with STS. Adoptive transfer of autologous T cells targeting NY-ESO-1 and MAGE-A4 have high response rates in sarcomas expressing these antigens, although recurrence is often seen in responding patients. Future work must focus on identifying primary and acquired mechanisms of resistance to these therapies, and extend T-cell receptor discovery to other tumor-associated antigens.
DNA methylation dynamics and dysregulation delineated by high-throughput profiling in the mouse
Authors: Wanding Zhou, Toshinori Hinoue, Bret Barnes, Owen Mitchell, Waleed Iqbal, Sol Moe Lee, Kelly K. Foy, Kwang-Ho Lee, Ethan J. Moyer, Alexandra VanderArk, Julie M. Koeman, Wubin Ding, Manpreet Kalkat, Nathan J. Spix, Bryn Eagleson, John Andrew Pospisilik, Piroska E. Szabó, Marisa S. Bartolomei, Nicole A. Vander Schaaf, Liang Kang, Ashley K. Wiseman, Peter A. Jones, Connie M. Krawczyk, Marie Adams, Rishi Porecha, Brian H. Chen, Hui Shen, Peter W. Laird
Journal: Cell Genomics (2022)

We have developed a mouse DNA methylation array that contains 296,070 probes representing the diversity of mouse DNA methylation biology. We present a mouse methylation atlas as a rich reference resource of 1,239 DNA samples encompassing distinct tissues, strains, ages, sexes, and pathologies. We describe applications for comparative epigenomics, genomic imprinting, epigenetic inhibitors, patient-derived xenograft assessment, backcross tracing, and epigenetic clocks. We dissect DNA methylation processes associated with differentiation, aging, and tumorigenesis. Notably, we find that tissue-specific methylation signatures localize to binding sites for transcription factors controlling the corresponding tissue development. Age-associated hypermethylation is enriched at regions of Polycomb repression, while hypomethylation is enhanced at regions bound by cohesin complex members. ApcMin/+ polyp-associated hypermethylation affects enhancers regulating intestinal differentiation, while hypomethylation targets AP-1 binding sites. This Infinium Mouse Methylation BeadChip (version MM285) is widely accessible to the research community and will accelerate high-sample-throughput studies in this important model organism.
Highlights of the NCCN Oncology Research Program
Authors: Sarbajit Mukherjee
Journal: Journal of the National Comprehensive Cancer Network (2022)

This is an open-label, multicenter, phase II study of trifluridine/tipiracil (FTD/TPI) administered with oxaliplatin before chemoradiation in patients with adenocarcinoma of the esophagus or gastroesophageal junction (GEJ).Patients meeting inclusion criteria will receive 3 cycles of FTD/TPI (35 mg/m 2 twice daily) and oxaliplatin (85 mg/m 2 ) before undergoing concurrent chemoradiation (standard-of-care radiation dose of 5,040 cGy will be used at all participating study sites) with carboplatin (area under the curve, 2) and paclitaxel (50 mg/m 2 ) for 6 weeks, followed by surgery.FTD/TPI will be self-administered (in tablet form) twice daily by study participants and documented in the provided drug diary.In this study, circulating tumor DNA (ctDNA) levels will be collected at 5 different time points: at diagnosis, after completion of induction chemotherapy, after completion of chemoradiation, after surgery, and at the time of disease recurrence, if this occurs.The aim is to correlate the ctDNA level with disease recurrence and metabolic response on PET/CT.Accrual is expected to take 24 months (N=45) with an additional 12 months of follow-up on study.After completion of 1 year of on-study follow-up, patients will be followed (monitored for survival status) as per standard of care: year 1 through year 2, every 3 to 6 months, every 6 to 12 months for 3 to 5 years, and then annually until disease progression or death, whichever occurs first.Estimated time frame for analysis of the primary endpoint is approximately 3 years after study commencement.
Breakthrough SARS-CoV-2 infections, morbidity, and seroreactivity following initial COVID-19 vaccination series and additional dose in patients with SLE in New York City
Authors: Amit Saxena, Alexis J Engel, Brittany Banbury, Ghadeer Hasan, Nicola Fraser, Devyn Zaminski, Mala Masson, Rebecca H Haberman, Jose U Scher, Gary Ho, Jammie Law, Paula Rackoff, Chung-E Tseng, H Michael Belmont, Robert M Clancy, Jill P Buyon, Peter M Izmirly
Journal: The Lancet Rheumatology (2022)
Using optimal foraging theory to infer how groups make collective decisions
Authors: Grace H. Davis, Margaret C. Crofoot, Damien R. Farine
Journal: Trends in Ecology & Evolution (2022)

Studying animal behavior as collective phenomena is a powerful tool for understanding social processes, including group coordination and decision-making. However, linking individual behavior during group decision-making to the preferences underlying those actions poses a considerable challenge. Optimal foraging theory, and specifically the marginal value theorem (MVT), can provide predictions about individual preferences, against which the behavior of groups can be compared under different models of influence. A major strength of formally linking optimal foraging theory to collective behavior is that it generates predictions that can easily be tested under field conditions. This opens the door to studying group decision-making in a range of species; a necessary step for revealing the ecological drivers and evolutionary consequences of collective decision-making.
Role of Radiation Therapy in Retroperitoneal Sarcoma
Authors: Kilian E. Salerno, Elizabeth H. Baldini
Journal: Journal of the National Comprehensive Cancer Network (2022)

Retroperitoneal sarcoma comprises a small subset of all soft tissue sarcoma and includes various histopathologic subtypes, each with unique patterns of behavior and differential risks for local recurrence and hematogenous metastatic spread. The primary treatment modality is surgery, although even with complete macroscopic resection, recurrence is common. The rationale for the addition of radiotherapy to resection is to improve local control; however, the use of radiation therapy for retroperitoneal sarcoma is controversial, and existing data are suboptimal to guide management. Treatment decisions should be determined with multidisciplinary input and shared decision-making. When used in selected patients, radiation therapy should be delivered preoperatively; postoperative treatment is not recommended.
Antibiotic prophylaxis versus no antibiotic prophylaxis in transperineal prostate biopsies (NORAPP): a randomised, open-label, non-inferiority trial
Authors: Maciej Jacewicz, Karsten Günzel, Erik Rud, Gunnar Sandbæk, Ahmed Magheli, Jonas Busch, Stefan Hinz, Eduard Baco
Journal: The Lancet Infectious Diseases (2022)
Disparities in Electronic Screening for Cancer-Related Psychosocial Distress May Promote Systemic Barriers to Quality Oncologic Care
Authors: Thomas L. Sutton, Marina Affi Koprowski, Jeffery A. Gold, Benjamin Liu, Alison Grossblatt-Wait, Caroline Macuiba, Andrea Lehman, Susan Hedlund, Flavio G. Rocha, Jonathan R. Brody, Brett C. Sheppard
Journal: Journal of the National Comprehensive Cancer Network (2022)

Screening for cancer-related psychosocial distress is an integral yet laborious component of quality oncologic care. Automated preappointment screening through online patient portals (Portal, MyChart) is efficient compared with paper-based screening, but unstudied. We hypothesized that patient access to and engagement with EHR-based screening would positively correlate with factors associated with digital literacy (eg, age, socioeconomic status).Screening-eligible oncology patients seen at our Comprehensive Cancer Center from 2014 through 2019 were identified. Patients with active Portals were offered distress screening. Portal and screening participation were analyzed via multivariable logistic regression. Household income in US dollars and educational attainment were estimated utilizing zip code and census data.Of 17,982 patients, 10,279 (57%) had active Portals and were offered distress screening. On multivariable analysis, older age (odds ratio [OR], 0.97/year; P<.001); male gender (OR, 0.89; P<.001); Black (OR, 0.47; P<.001), Hawaiian/Pacific Islander (OR, 1.54; P=.007), and Native American/Alaskan Native race (OR, 0.67; P=.04); Hispanic ethnicity (OR, 0.76; P<.001); and Medicare (OR, 0.59; P<.001), Veteran's Affairs/military (OR, 0.09; P<.01), Medicaid (OR, 0.34; P<.001), or no insurance coverage (OR, 0.57; P<.001) were independently associated with lower odds of being offered distress screening; increasing income (OR, 1.05/$10,000; P<.001) and educational attainment (OR, 1.03/percent likelihood of bachelor's degree or higher; P<.001) were independently associated with higher odds. In patients offered electronic screening, participation rate was 36.6% (n=3,758). Higher educational attainment (OR, 1.01; P=.03) was independently associated with participation, whereas Black race (OR, 0.58; P=.004), Hispanic ethnicity (OR, 0.68; P=.01), non-English primary language (OR, 0.67; P=.03), and Medicaid insurance (OR, 0.78; P<.001) were independently associated with nonparticipation.Electronic portal-based screening for cancer-related psychosocial distress leads to underscreening of vulnerable populations. At institutions using electronic distress screening workflows, supplemental screening for patients unable or unwilling to engage with electronic screening is recommended to ensure efficient yet equal-opportunity distress screening.
The Risk of Opportunistic Infections and the Role of Antibiotic Prophylaxis in Patients on Checkpoint Inhibitors Requiring Steroids
Authors: Neil J. Shah, Michael R. Cook, Tianmin Wu, Shaked Lev-Ari, Matthew J. Blackburn, Michael T. Serzan, Adil Alaoui, Jaeil Ahn, Michael B. Atkins
Journal: Journal of the National Comprehensive Cancer Network (2022)

Immune-related adverse events (irAEs) often require treatment with high-dose systemic steroids (SS) and other immunosuppressive agents (ISAs). NCCN Guidelines recommend prophylactic antibiotics for Pneumocystis jirovecii pneumonia (PJP) for patients receiving prolonged SS/ISAs. However, there is a paucity of evidence regarding the incidence of opportunistic infections (OIs) and non-OIs and the role of prophylactic antibiotics in patients on SS/ISAs for irAEs.A retrospective analysis was conducted of patients treated using immune checkpoint inhibitor (ICI) therapy at 5 MedStar Health hospitals from January 2011 to April 2018. OIs were defined per the Infectious Diseases Society of America guidelines for the prevention and treatment of OIs in patients with HIV. The study cohort included patients who received ≥20 mg daily of a prednisone equivalent for ≥4 weeks to manage irAEs.The study cohort identified 112 (15%) of 758 total patients treated using ICIs. Baseline characteristics included the following: median age was 64 years, 74% (n=82) of patients were White, 89% (n=100) had an ECOG performance status ≤1, 61% (n=68) had melanoma, 19% (n=21) had non-small cell lung cancer, 45% (n=50) were treated using an anti-PD-(L)1 ICI, and 33% (n=37) were treated using an anti-PD-1/anti-CTLA-4 combination. The median starting SS dose was 100 mg of a prednisone equivalent, and 25% of patients required additional ISAs, with infliximab (n=15) and mycophenolate mofetil (n=9) being the most common. We found that 20% (n=22) of patients developed any infection, including 7% (n=8) with OIs (oral candidiasis [n=4], nondisseminated varicella zoster infection [n=2], PJP [n=1], and Listeria monocytogenes endophthalmitis [n=1]) and 13% (n=14) with non-OIs (most common: Clostridium difficile and pneumonia [n=5 each]). PJP prophylaxis with sulfamethoxazole/trimethoprim was given to 13% (n=14) patients, of whom 43% (n=6) developed OIs/non-OIs.Our study highlights the fundamental issues for patients on ICI therapy who require SS/ISAs for irAEs: the degree of immunosuppression and the relative risk of OI. We noted a low incidence of OIs overall and breakthrough infections despite PJP prophylaxis. We question whether PJP prophylaxis is efficacious or necessary. Prospective trials are required to answer these questions.
Neoadjuvant Radiotherapy After (m)FOLFIRINOX for Borderline Resectable Pancreatic Adenocarcinoma: A TAPS Consortium Study
Authors: Quisette P. Janssen, Jacob L. van Dam, Laura R. Prakash, Deesje Doppenberg, Christopher H. Crane, Casper H.J. van Eijck, Susannah G. Ellsworth, William R. Jarnagin, Eileen M. O’Reilly, Alessandro Paniccia, Marsha Reyngold, Marc G. Besselink, Matthew H.G. Katz, Ching-Wei D. Tzeng, Amer H. Zureikat, Bas Groot Koerkamp, Alice C. Wei, _ _
Journal: Journal of the National Comprehensive Cancer Network (2022)

The value of neoadjuvant radiotherapy (RT) after 5-fluorouracil with leucovorin, oxaliplatin, and irinotecan, with or without dose modifications [(m)FOLFIRINOX], for patients with borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) is uncertain.
IL-15 blockade and rapamycin rescue multifactorial loss of factor VIII from AAV-transduced hepatocytes in hemophilia A mice
Authors: John S.S. Butterfield, Kentaro Yamada, Thais B. Bertolini, Farooq Syed, Sandeep R.P. Kumar, Xin Li, Sreevani Arisa, Annie R. Piñeros, Alejandro Tapia, Christopher A. Rogers, Ning Li, Jyoti Rana, Moanaro Biswas, Cox Terhorst, Randal J. Kaufman, Ype P. de Jong, Roland W. Herzog
Journal: Molecular Therapy (2022)

Hepatic adeno-associated viral (AAV) gene transfer has the potential to cure the X-linked bleeding disorder hemophilia A. However, declining therapeutic coagulation factor VIII (FVIII) expression has plagued clinical trials. To assess the mechanistic underpinnings of this loss of FVIII expression, we developed a hemophilia A mouse model that shares key features observed in clinical trials. Following liver-directed AAV8 gene transfer in the presence of rapamycin, initial FVIII protein expression declines over time in the absence of antibody formation. Surprisingly, loss of FVIII protein production occurs despite persistence of transgene and mRNA, suggesting a translational shutdown rather than a loss of transduced hepatocytes. Some of the animals develop ER stress, which may be linked to hepatic inflammatory cytokine expression. FVIII protein expression is preserved by interleukin-15/interleukin-15 receptor blockade, which suppresses CD8
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Authors: Tybjaerg Liv, Børge Nordestgaard, Anne Nordestgaard, L Nordestgaard, Anne Tybjaerg-Hansen
Journal: JAMA Cardiology (2022)

Behnood Bikdeli, MD, MS; Farbod Zahedi Tajrishi, MD; Parham Sadeghipour, MD; Azita H. Talasaz, PharmD; John Fanikos, RPH, MBA; Giuseppe Lippi, MD; Deborah M. Siegal, MD, MSc; John W. Eikelboom, MBBS; Manuel Monreal, MD, PhD; David Jimenez, MD, PhD; Jean M. Connors, MD; Walter Ageno, MD, PhD; Geoffrey D. Barnes, MD, MSc; Gregory Piazza, MD, MS; Dominick J. Angiolillo, MD, PhD; Sahil A. Parikh, MD; Ajay J. Kirtane, MD, SM; Renato D. Lopes, MD, PhD; Deepak L. Bhatt, MD, MPH; Jeffrey I. Weitz, MD; Roxana Mehran, MD; Harlan M. Krumholz, MD, SM; Samuel Z. Goldhaber, MD; Gregory Y. H. Lip, MD
DAMP-modulating nanoparticle for successful pancreatic islet and stem cell transplantation
Authors: Soo Bin Jang, Sang-Man Jin, Hyung Shik Kim, Yong Yeon Jeong, Sang Jun Lee, Soojung Hahn, Hyemin Lee, Han Sin Lee, Jae Hyeon Kim, Dong Yun Lee
Journal: Biomaterials (2022)
Incorporating family history of disease improves polygenic risk scores in diverse populations
Authors: Margaux L.A. Hujoel, Po-Ru Loh, Benjamin M. Neale, Alkes L. Price
Journal: Cell Genomics (2022)

Polygenic risk scores (PRSs) derived from genotype data and family history (FH) of disease provide valuable information for predicting disease risk, but PRSs perform poorly when applied to diverse populations. Here, we explore methods for combining both types of information (PRS-FH) in UK Biobank data. PRSs were trained using all British individuals (n = 409,000), and target samples consisted of unrelated non-British Europeans (n = 42,000), South Asians (n = 7,000), or Africans (n = 7,000). We evaluated PRS, FH, and PRS-FH using liability-scale R2, primarily focusing on 3 well-powered diseases (type 2 diabetes, hypertension, and depression). PRS attained average prediction R2s of 5.8%, 4.0%, and 0.53% in non-British Europeans, South Asians, and Africans, confirming poor cross-population transferability. In contrast, PRS-FH attained average prediction R2s of 13%, 12%, and 10%, respectively, representing a large improvement in Europeans and an extremely large improvement in Africans. In conclusion, including family history improves the accuracy of polygenic risk scores, particularly in diverse populations.
SNP-to-gene linking strategies reveal contributions of enhancer-related and candidate master-regulator genes to autoimmune disease
Authors: Kushal K. Dey, Steven Gazal, Bryce van de Geijn, Samuel Sungil Kim, Joseph Nasser, Jesse M. Engreitz, Alkes L. Price
Journal: Cell Genomics (2022)

We assess contributions to autoimmune disease of genes whose regulation is driven by enhancer regions (enhancer-related) and genes that regulate other genes in trans (candidate master-regulator). We link these genes to SNPs using several SNP-to-gene (S2G) strategies and apply heritability analyses to draw three conclusions about 11 autoimmune/blood-related diseases/traits. First, several characterizations of enhancer-related genes using functional genomics data are informative for autoimmune disease heritability after conditioning on a broad set of regulatory annotations. Second, candidate master-regulator genes defined using trans-eQTL in blood are also conditionally informative for autoimmune disease heritability. Third, integrating enhancer-related and master-regulator gene sets with protein-protein interaction (PPI) network information magnified their disease signal. The resulting PPI-enhancer gene score produced >2-fold stronger heritability signal and >2-fold stronger enrichment for drug targets, compared with the recently proposed enhancer domain score. In each case, functionally informed S2G strategies produced 4.1- to 13-fold stronger disease signals than conventional window-based strategies.
Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling
Authors: Hongxu Xian, Kosuke Watari, Elsa Sanchez-Lopez, Joseph Offenberger, Janset Onyuru, Harini Sampath, Wei Ying, Hal M. Hoffman, Gerald S. Shadel, Michael Karin
Journal: Immunity (2022)

Mitochondrial DNA (mtDNA) escaping stressed mitochondria provokes inflammation via cGAS-STING pathway activation and, when oxidized (Ox-mtDNA), it binds cytosolic NLRP3, thereby triggering inflammasome activation. However, it is unknown how and in which form Ox-mtDNA exits stressed mitochondria in non-apoptotic macrophages. We found that diverse NLRP3 inflammasome activators rapidly stimulated uniporter-mediated calcium uptake to open mitochondrial permeability transition pores (mPTP) and trigger VDAC oligomerization. This occurred independently of mtDNA or reactive oxygen species, which induce Ox-mtDNA generation. Within mitochondria, Ox-mtDNA was either repaired by DNA glycosylase OGG1 or cleaved by the endonuclease FEN1 to 500–650 bp fragments that exited mitochondria via mPTP- and VDAC-dependent channels to initiate cytosolic NLRP3 inflammasome activation. Ox-mtDNA fragments also activated cGAS-STING signaling and gave rise to pro-inflammatory extracellular DNA. Understanding this process will advance the development of potential treatments for chronic inflammatory diseases, exemplified by FEN1 inhibitors that suppressed interleukin-1β (IL-1β) production and mtDNA release in mice.